Historically, most medical gases which are considered to be pharmaceuticals by the Food and Drug Administration (FDA) whether they are USP grade or NF grade or have undergone a New Drug Approval (NDA) are supplied in the form of compressed gas cylinders, generally containing large gas volumes and for return and refilling by distributors and the like. These large cylinders create significant problems in terms of their handling and use, as well as their shipment which is generally as hazardous materials.
One exception to this is oxygen gas. Oxygen has had a long history of use by outpatients and home care patients in the form of small as well as large compressed gas cylinders. In addition, heliox, a mixture generally of 40% to 80% helium in oxygen has also sometimes been made available to home care patients.
Other gases which have been used to some extent for medical purposes such as N2O are rarely used on a home care basis and particularly are not permitted for self administration because of the dangers involved and the inability to control their use. Once again, as a general matter, with the use of medical gases including N2O in oxygen or air and other such gases, even when provided in connection with dental procedures, or during ambulance transport and the like, the gas is generally applied by professionals or in the presence of a professional on a relatively long-term basis ranging from 15 minutes to several hours. There are, in fact, other reasons why large compressed gas cylinders themselves have not been used on an outpatient basis, including the ease of access to the contents of such cylinders with standard valves, for recreational abuse in the case of certain medical gases such as N2O, risk of overdosing, and other safety reasons such as enhanced flammability for certain gases and the like. In addition, these systems require the use of separate gas pressure regulators and/or blenders in order to assist in the application of these gases, and none of these known systems is present for the administration of therapeutic gases for short periods of time for specific medical purposes, and particularly not in an outpatient or home environment for self application.
Certain medical gases with therapeutic effects, such as nitrous oxide and xenon, are subject to potential recreational misuse and abuse. Cylinders of nitrous oxide and/or xenon containing large volumes of the gas and easy access to the cylinder contents by the use of traditional valves may be attractive to such non-prescribed use, or outright theft from a non-medical location, such as a patient's home, and is a major reason, in addition to concerns about overdosing, that such gases are limited to use at medical sites where security and medical supervision exists. Compressed gas cartridges containing these two gases, because of their size and the fact that they utilize a standardized, easily accessed surface for puncture and release of their contents, may be particular targets for recreational use. This is a key reason why medical gases, and in particular those with the potential for recreational abuse such as N2O or Xe, have never been approved for packaging and marketing in compressed gas cartridges. Therefore, it is highly desirable to have a sealed unit dose package and a means of delivery as described below that is strongly tamper, abuse and misuse resistant, incorporates multiple levels of safety or fail safe mechanisms, and which includes the ability to comply with new FDA regulations concerning unit dose pharmaceutical traceability as FDA considers medical gases to be regulated as pharmaceuticals.
U.S. Pat. No. 6,016,801 discloses a device for the delivery of nitrous oxide as an alternative to smoking, and to serve as a stress-reducing, recreational and nonaddictive smoking substitute. The delivery system in U.S. Pat. No. 6,016,801 mixes the nitrous oxide with ambient air from outside the device. The device includes a nitrous oxide container which includes a refilling port, and there is no discussion in this patent of the nature or duration of administration thereof. Furthermore, the device described in this patent also does not address issues of safety and control regarding the potential for misuse or recreational abuse of N2O that would be required for approval by a regulatory body such as the FDA, and therefore is not applicable to practical medical use.
U.S. Pat. No. 6,125,844 discloses a hand-held delivery system which delivers oxygen or oxygen along with a medication, so that the oxygen can act as a propellant and as a therapeutic agent in its own right. The device used in U.S. Pat. No. 6,125,844 includes a pressurized gas supply 12 in which the single gas canister can be replaced, and is said to include the possibility of other gases listed therein.
International Application No. WO 01/36018 discloses a device for the co-application of drugs, such as in a powdered form, along with short bursts of a vapor or gas, primarily CO2. This device is not used for the normal respiration of a pure gas or gas mixture, but is intended to utilize a small CO2 canister to entrain the drug for application to the patient's nose, mouth, eye, etc. This device is not intended for the normal respiration of a medical gas for any significant time period, and cannot accommodate a gas mixture for such purposes. A similar device is shown in International Application No. WO 01/03645 for bathing the mucous membranes of the body with a gas such as CO2. In addition, U.S. Pat. No. 6,484,664 discloses a holder for a device for consumable products, such as a CO2 cartridge, which includes a mechanism whereby the amount of remaining product in the dispenser can be determined based on the center of mass of the device.
Additional commercial systems for the supply of various gases and gas mixtures are also available. The NITRONOX unit from Matrx Medical, using pressure reducing regulators and a blending system combines N2O and O2 from separate compressed gas cylinders into a fixed mixture of 50% N2O and 50% O2 which is delivered to the patient using a demand valve and face mask. More than about a 30-minute supply of nitrous oxide is mixed with the oxygen, but this allegedly “portable” system has a weight of over 12 pounds, requires an external and separate O2 source, which may be a compressed gas cylinder whose weight is not included in the above 12 pounds, or a wall outlet O2 source, and also requires supervision by medical personnel trained in its use when it is self administered by a patient using the demand valve and face mask due to the medical management required in order to operate the NITRONOX blending device itself. Additional systems include the MEDIMIX unit of AGA Linde Health Care which includes a single premixed cylinder with 50 mole percent nitrous oxide and 50 more percent oxygen with a regulator, tubing, a demand valve and a face mask, and other elements, as well as the ENTONOX unit from BOC, Inc., which again requires medical personnel for use and has a weight and a size making it impossible to be carried and used with a single hand in a portable manner, and is therefore not usable for self-administration by an outpatient at home, work or other locations.
Other gases have also been utilized for patient treatment and in similar types of systems. U.S. Pat. No. 5,228,434, for example, discloses a system for the application of xenon in admixture with oxygen and helium as an anesthetic gas for administration during relatively long periods of time, such as that involved in surgical procedures.
U.S. Pat. No. 5,846,556 describes inhalant compositions for relaxation or the reduction of stress therewith. The preferred composition disclosed in this patent includes nitrogen and oxygen, and can include additional inert gases such as helium and xenon. In a preferred embodiment of this invention, the gas comprises nitrogen, oxygen, neon, argon, carbon dioxide and nitrous oxide. The patentee discloses that the inhalant can be packaged, for example, in a pressurized tank or in small pressurized containers for portable personal use. It is also stated that the product can be used for from one to 10 minutes twice per day. A number of the specific gases collectively provided in the preferred embodiment on a quantified basis provided no added medical and/or other benefit within the collective mixture.
U.S. Pat. No. 5,690,968 discloses an analgesic anesthetic composition, preferably including equal volumes of nitrous oxide and oxygen. The background of this patent discusses a prior system sold under the trademark ENTONOX which includes a demand valve by which the gas can be self-administered by a patient. The invention disclosed in this patent includes an additional ether-based anesthetic which is said to be disposable in a single container above its pseudo-critical temperature at a pressure of 2,000 psi, forming a homogeneous analgesic anesthetic composition. Use of such a product by an outpatient, or supervised by a medical person, is highly unlikely due to safety and other regulatory issues generated by the inclusion of the ether-based anesthetic in the mixture. Furthermore, in locations of treatment where medical persons are present such as hospitals, clinics and emergency medical services ambulances, the likely cost of producing and obtaining regulatory approval of such a product would require product pricing which renders alternatives that provide medical benefit of relatively equal treatment value to be far more attractive in an era of cost consciousness.
U.S. Pat. No. 2,185,067 discloses apparatus for self-administration of nitrous oxide/oxygen mixtures for analgesic purposes. This patent discloses use of this apparatus for short-term procedures. The device includes a pair of gas cylinders with pressure reducing and mixing equipment therefor.
U.S. Pat. No. 3,747,600 discloses an anesthetic apparatus for supplying oxygen/nitrous oxide gas mixtures that is primarily intended for attachment to the wall of a room in which administration is to take place, and the sources of N2O and O2 include both wall outlets, and large cylinders. The device includes a homogeneous block of metal which is said to produce a very compact, light-weight version of the anesthetic apparatus, for example, one which is 5×5×15 cm, not including the reservoir bag and lever tube, and which can be attached to a wall or stand.
U.S. Pat. No. 5,485,827 discloses the administration of nitric oxide for the treatment of asthma and the like in which the gas is administered for at least three minutes, and preferably at least six minutes. This patent discloses an inhalation device as shown in FIGS. 17 and 18 in which vessel 12 includes a pressurized gas with at least 1 ppm nitric oxide dissolved in a liquefied propellant or compressed inert gas with a rebreathing chamber 22, and the total weight of the device is said to be less than 200 grams so that it is readily portable.
U.S. Pat. No. 6,164,276 discloses apparatus for delivering precise volumes of a therapeutic gas; namely, nitric oxide. The device in this patent uses a sensing device for detecting the start of a patient's spontaneous breathing for purposes of gas control regulation.
U.S. Pat. No. 5,488,946 discloses an emergency breathing supply apparatus which includes two high pressure air cartridges supplying air through demand regulators. The device is specifically for emergency purposes, so as to supply from six to eight minutes of breathable air from these cartridges.
U.S. Pat. No. 6,021,777 discloses a portable anesthesia machine which includes apparatus for delivering a mixture of oxygen and nitrous oxide combined with any known industry standard liquid anesthesia agents. This machine is said to be insensitive to the physical attitude of the machine, and is said to be transportable.
U.S. Pat. No. 6,286,505 discloses a portable anesthetic machine that utilizes liquid anesthetic and is used with an emergency kit which is said to be usable in rapid treatment of or surgery on acutely injured patients.
U.S. Pat. No. 4,648,393 discloses a breath-activated inhaler in which a pin releases a metered dose of medication for direct inhalation by the patient.
One particular area of particular application for therapeutic gases on a portable, handheld self-administration basis is in connection with atrial fibrillation implantable cardioverter defibrillators or AF-ICDs, or multi-function implants which include AF-ICD capability, which have been implanted in patients who then return to their normal lives and on an outpatient basis detect atrial fibrillation, notify the patient, and allow self-activation of a shock on a timer to effect atrial defibrillation. In connection with this procedure, there is a significant need for a co-therapy so that outpatients can reduce pain, anxiety and phobia related to self-administration of a shock of this type. It is also necessary to apply the co-therapy quickly, for it to provide a rapid onset of analgesic, anxiolytic and anteragrade amnesic effects which begin prior to, last during and immediately after the atrial defibrillating shock, rapidly dissipate after use so that the patient returns to normal sensorium and can quickly resume daily routine activities supporting a quality of life, and to be safe and easy to use in this manner.
Therapeutic gases and gas mixtures are known in the art. Examples include oxygen, nitrous oxide, xenon, helium, carbon dioxide, and mixtures thereof.